chr7-45000377-G-A

Variant names:

• chr7-45000377-G-A
• rs1795543777
• NM_031443.4:c.30+14G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_031443.4(CCM2):​c.30+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000676 in 147,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCM2 NM_031443.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.244
• Publications: 0 publications found

Genes affected

CCM2 (HGNC:21708): (CCM2 scaffold protein) This gene encodes a scaffold protein that functions in the stress-activated p38 Mitogen-activated protein kinase (MAPK) signaling cascade. The protein interacts with SMAD specific E3 ubiquitin protein ligase 1 (also known as SMURF1) via a phosphotyrosine binding domain to promote RhoA degradation. The protein is required for normal cytoskeletal structure, cell-cell interactions, and lumen formation in endothelial cells. Mutations in this gene result in cerebral cavernous malformations. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]

CCM2 Gene-Disease associations (from GenCC):

• cerebral cavernous malformation 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• famililal cerebral cavernous malformations

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 7-45000377-G-A is Benign according to our data. Variant chr7-45000377-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3680207.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031443.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	NM_031443.4	MANE Select	c.30+14G>A		intron	N/A	NP_113631.1	Q9BSQ5-1
	CCM2	NM_001363458.2		c.30+14G>A		intron	N/A	NP_001350387.1
	CCM2	NM_001363459.2		c.30+14G>A		intron	N/A	NP_001350388.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCM2	ENST00000258781.11	TSL:1 MANE Select	c.30+14G>A		intron	N/A	ENSP00000258781.7	Q9BSQ5-1
	CCM2	ENST00000938553.1		c.30+14G>A		intron	N/A	ENSP00000608612.1
	CCM2	ENST00000956241.1		c.30+14G>A		intron	N/A	ENSP00000626300.1

Frequencies

GnomAD3 genomes AF: 0.00000676 AC: 1 AN: 147990 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000494

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1145970 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 552600

African (AFR) AF: 0.00 AC: 0 AN: 23820

American (AMR) AF: 0.00 AC: 0 AN: 13796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17066

East Asian (EAS) AF: 0.00 AC: 0 AN: 26922

South Asian (SAS) AF: 0.00 AC: 0 AN: 30822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3146

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 947174

Other (OTH) AF: 0.00 AC: 0 AN: 45754

GnomAD4 genome AF: 0.00000676 AC: 1 AN: 147990 Hom.: 0 Cov.: 24 AF XY: 0.0000139 AC XY: 1 AN XY: 72004

African (AFR) AF: 0.00 AC: 0 AN: 40186

American (AMR) AF: 0.00 AC: 0 AN: 14888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 4942

South Asian (SAS) AF: 0.00 AC: 0 AN: 4692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66590

Other (OTH) AF: 0.000494 AC: 1 AN: 2026

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cerebral cavernous malformation 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.2
DANN	Benign	0.94
PhyloP100		0.24
PromoterAI		0.059	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1795543777; hg19: chr7-45039976;